Albert Hofmann (1906 – 2008) – an Obituary

Albert Hofmann, 102, Swiss chemist, father of LSD, honorary member of ASP and GA and Dr. h. c. mult. (ETH Zurich, Free University of Berlin, Royal Institute of Technology in Stockholm), died April 29, 2008 – four months after his beloved wife Anita – at his home in Burg, a village near Basel, Switzerland.

Hofmann was born in Baden, a spa and industrial town near Zurich, on January 11, 1906. After a commercial apprenticeship he studied chemistry at the University of Zurich under the direction of Professor Paul Karrer, a future Nobel laureate. His doctoral thesis dealt with the structure elucidation of chitin, the cellulose-like structural material found in numerous classes of animals, such as insects and crustaceans. Hofmann discovered that an enzyme preparation from Helix pomatia efficiently degraded chitin and conclusively demonstrated that it was a polymer of N-acetylglucosamine [1].

After completing his PhD thesis he joined Sandoz in Basel in 1929 as he had a vivid interest in this company’s research program – isolation and synthesis of the active principles from medicinal plants for the development of plant-based medicines. He worked in the pharmaceutical/chemical research laboratories of Sandoz until his retirement in 1971, first as a coworker of Prof. Arthur Stoll, later as a group leader and finally – for the last 15 years of his career – as head of the natural products department. His early research at Sandoz was on the chemistry of cardiac glycosides from squill (Scilla maritima). At that time, ill defined Digitalis and Scilla preparations were in use, and scientists at Sandoz were aiming at chemically defined preparations for safer use. He was involved in the isolation of scillaren A, the first pure glycoside from squill [2], in studies on the enzymatic degradation of cardiac glycosides [3], and later was able to demonstrate the gross structure of the bufadienolide [4].

In 1935, Hofmann moved on to a promising new field, the ergot alkaloids. There was a history in ergot research at Sandoz, as Stoll himself had isolated the first ergot alkaloid, ergotamine, in 1918 already. The compound had been in use since 1921 under the trade name Gynergen® for stopping of postpartum bleeding, later also for the treatment of migraine. Hofmann’s initial focus was on a practical synthesis of ergometrine (ergobasine). This minor alkaloid had been identified shortly before by three research groups, one of them at Sandoz, as a strongly uterotonic substance in ergot. Hofmann achieved the synthesis via hydrolysis of ergotamine to lysergic acid, which in turn was derivatised to its propanolamide. It was the first synthesis of an ergot alkaloid, and a practical route to numerous lysergic acid derivatives [5], [6]. One of these derivatives, methylergometrine (Methergin®), was developed for control of postpartum bleeding, as it had a better pharmacological profile than the natural product ergometrine. In 1938, Hofmann synthesised another derivative, lysergic acid diethylamide (LSD), which eventually was to become his most famous compound. However, he discovered its potent psychotropic activity only a few years later, and rather by chance, in a self-experiment conducted on April 19^th, 1943 [7]. His bicycle ride home from the laboratory on that day has passed into drug lore as the first LSD trip. Subsequently he became world-renowned as the father of LSD. The discovery of LSD opened the door to psychopharmacology, and paved the way for the understanding of the biochemistry of the neurotransmitters serotonin and dopamine during the following decades.

After its discovery, LSD was viewed as a wonder drug with the potential to treat psychical problems including schizophrenia. Under the name of Delyside® it was studied clinically for ten years and showed great promise as a pharmacological aid in psychoanalysis. However, LSD not only elicited great interest among psychiatrists but also became the preferred drug of hippie and other subcultures, and found expression in the fine arts and in the music. The partly uncontrolled consumption led to a global ban of LSD in the sixties, even of its use for therapeutic and scientific purposes. According to Dr. Hofmann this decision was politically motivated rather than scientifically.

From an industrial viewpoint, other discoveries in ergot research proved to be of significant importance. Hofmann demonstrated that ”ergotoxine” was in fact a variable mixture of three structurally related compounds which he named ergocristine, ergocryptine and ergocornine [8]. In the same year, he published a method for the practical catalytic hydrogenation of ergot alkaloids [9]. This seemingly minor structural modification had far reaching consequences, as the dihydro derivatives showed significantly improved stability against degradation by light and oxygen, and had a profoundly altered pharmacological profile compared to the natural alkaloids. Dihydroergotoxine (Hydergine®) was initially introduced as a drug for the treatment of hypertension and circulatory disorders and later became a major commercial success for Sandoz when it was used as a nootropic to improve cerebral blood flow in elderly patients. Dihydroergotamine (Dihydergot®) is used up to now as a drug to treat orthostatic hypotention and migraine.

In the late 1940s, the structures of the ergot alkaloids were still incompletely known. Hoffmann and his coworkers investigated the stereochemistry of the lysergic acid moiety and its isomerisation reactions to pharmacologically inactive compounds [10], [11], and later turned their attention to the tricyclic peptide moiety of the ergopeptines. In 1951, the full structures of ergotamine and related alkaloids were published [12]. This line of research culminated a few years later in the successful total synthesis of ergotamine [13], [14]. In a parallel effort, the reactivity of lysergic acid was systematically explored and numerous derivatives prepared and tested. Halogenation reactions turned out to produce compounds with unique pharmacological profiles [15]. Among these, bromocryptine (Parlodel®) was a potent dopaminergic and became a drug for treatment of hyperprolactinaemia and Parkinson's disease. The compound inspired other pharmaceutical companies in the development of ergolin-based anti-Parkinson dopamine agonists, such as cabergoline, lisuride and pergolide.

With the increasing demand for ergot alkaloids, securing the production became a serious issue. Initially, ergot alkaloids were extracted from Claviceps sclerotia obtained from artificially inoculated rye fields. Initial studies on the fermentative production of ergot alkaloids were conducted at Sandoz in the 1950s [16], [17] and paved the way for submerged cultures of C. purpurea for production of peptide type alkaloids, and C. paspali for the production of paspalic acid as a starting material for partial synthesis.

When Ciba, one of the other major pharmaceutical industries in Basel, introduced reserpine (Serpasil®) in 1953 as one of the first effective antipsychotic and antihypertensive drugs, Sandoz also embarked on a Rauvolfia project. Given the indolic nature and pharmacological profile of reserpine, there were obvious common features with the ergot alkaloids. Hofmann and his team isolated and characterised a number of new alkaloids [18], even though this effort eventually did not result in a drug.

In the meantime, Albert Hofmann was well known among scientists for his discovery of the psychoactive LSD and, therefore, was approached by the French mycologist Roger Heim who sought his chemical expertise on hallucinogens. Gordon Wasson, an American banker, and his wife had witnessed in Mexico the use of the psychoactive mushroom ”Teonanacatl”, which Heim identified as a new Psilocybe species. As a first step, the team at Sandoz established that the psychotropic properties of the fruiting body were also present in mycelial cultures. This ensured sufficient supply of raw material for the chemical investigation. Hofmann isolated the psychotropic compounds in an activity directed approach. Given that animal testing with mice and dogs were not conclusive, Hofmann followed the activity by testing the effect on himself and on some volunteers among his colleages at Sandoz [19], [20]. Finally, two indole phosphoric esters, psilocine and psilocybine, were identified. Pharmacological investigations later clarified their serotoninergic mode of action as mixed 5-HT_1A/2A receptor agonists.

Shortly after, Hofmann elucidated the mystery of another Mexican psychotropic drug, ”Ololiuqui”. This sacred drug of the Aztecs had been identified as Rivea corymbosa (L.) Hall. f.. Hofmann discovered that the psychoactive principles in the seeds were lysergic acid amide and related compounds [21]. This was the first discovery of lysergic acid derivatives in higher plants and, as such, a major surprise at that time. One assumes today that this unusual occurrence of ergolin-derived natural products in some species of the Convolvulaceae family is due to endophytic fungi.

One of Hofmann’s last publications at Sandoz surprisingly dealt with the characterization of a new structural class of artificial sweeteners [22]: During the synthesis of model compounds of lysergic acid, one derivative with intensive sweetness had been found. The compound, named ”glycergic acid”, was sweeter than saccharin, had no unpleasant aftertaste and low acute toxicity. However, the compound was not developed further despite its favourable properties.

Albert Hofmann’s career as chemist had been largely centred on the indole moiety as a scaffold of structurally diverse natural products and semi synthetic derivatives with an equally diverse spectrum of pharmacological properties. He synthesised an impressive number of compounds which eventually became highly successful drugs and established the indole moiety as what contemporary medicinal chemistry would designate as ”priviledged structure”. Indeed, Hofmann’s legacy influenced medicinal chemistry efforts at Sandoz even years after his retirement, as reflected in the development of several (fully synthetic) drugs containing the indole moiety as a structural motif, such as the β-blocker pindolol (Visken®), tropisetron (Navoban®), a selective antagonist at neuronal serotonin receptors used as an antiemetic, and tegaserod (Zelmac®), a drug against irritable bowel syndrome.

Albert Hofmann authored more than hundred scientific papers and several books. He published an extensive account on the complex chemistry of ergot alkaloids in his book ”Die Mutterkornalkaloide” [23]. The legendary story of the LSD discovery and the initial experiments in humans are vividly recounted by Hofmann in his book ”LSD – mein Sorgenkind” (1979) which was translated into English as ”LSD – My Problem Child” (1980) [7]. LSD was surely the most sensational of all compounds ever synthesised in Basel, and the most powerful psychotropic substance known.

After his retirement from professional life, he increasingly devoted himself to philosophical reflections on the experience of nature, publishing a collection of assays ”Einsichten– Ausblicke” (published in English as ”Insight –Outlook”) [24] as well as an illustrated volume entitled ”Lob des Schauens” (”In Praise of Contemplation”) [25]. His fundamental credo is published in ”Insight – Outlook”: ”I believe that the significance of the natural sciences in the evolution of human society does not lie primarily in the fact that they provided the basis for the development of modern technologies and industries that have radically changed our lives and our planet, but rather in the fact that they can open people’s eyes to the wonder of creation and to the unity of all life on earth, of which humanity is a part. If this knowledge fully entered public consciousness, it could form the basis of a new spirituality and help to resolve our current spiritual, social and environmental problems”.

In 2007 Hofmann was elected by the readers of the English newspaper ”Guardian” as one of the ”world’s top 10 living geniuses”. In celebration of Albert Hofmann’s 100th birthday (January 11, 2006) a book of a special kind ”Grenzgänge” (”Exploring the frontiers”) [26] has been written by his friends to pay tribute to the scientist and man. Dr. Hofmann was not only a scientist with a philosophical bent; he had also remained until the end of his life a cheerful and good-humoured man. Everyone was impressed by his phenomenal knowledge not only of chemistry and physics but also of literature, music and arts in general. He enjoyed long restorative walks in the woods around his beautiful house in the countryside, read books of baroque literature in the original and corresponded with friends and colleagues around the world.

Albert Hofmann was always convinced that only physicians should handle LSD and other psychedelic drugs. He was deeply disappointed by the worldwide ban of LSD also in therapy and research in the sixties. So it is not surprising that he judged the approval in 2007 of an LSD study in Switzerland, the first trial in the past 35 years, as a fulfillment of a dream.

Albert Hofmann was appointed as the 8^th Honorary Member of GA, on the occasion of the 25^th Annual Meeting 1977 at ETH Zurich, for his outstanding and successful research especially on digitaloids from Urginea maritima as well as on ergot and Rauvolfia alkaloids, including the synthesis of LSD and the discovery of its psychotropic activities. Since the early years of GA Hofmann was involved in the activities of the society. He was member of the Advisory Board in the years 1960/1961. Hofmann was invited several times as plenary lecturer, e. g. at the 5^th annual GA meeting 1957 in Würzburg (Chemistry of Rauvolfia alkaloids), the 6^th annual GA meeting in Tübingen (The chemistry of ergot alkaloids), the 8^th annual GA meeting 1960 in Braunschweig (Chairman of the symposium ”Constituents of Fungi”), the 9^th annual meeting 1961 in Bad Oeynhausen (The active constituents of the Mexican ”magical” plant Ololiuqui), the 12^th annual GA meeting 1964 in Berlin (Mexican ”magical” plants and their constituents), the 2^nd Joint Meeting with ASP/23^rd annual GA meeting 1975 in Storrs, USA (Discovery of LSD), and the 29^th annual meeting 1982 in Marburg (Hallucinogenic drugs as psychoactive drugs). Besides, Albert Hofmann frequently attended GA meetings as regular participant (19^th, 26^th, 28^th, 30^th, 32^nd, 34^th, 37^th, 40^th, 41^st, 43^rd and 46^th). On the occasion of the 30^th annual meeting 1982 in Graz he wrote in a letter to the GA president at that time (Prof. O. Sticher) that he enjoyed participating in the scientific meetings of GA and appreciated very much to cultivate friendship with colleagues. At the age of 92, Albert Hofmann attended for the last time a GA congress (46^th annual meeting in Vienna).

References

• 1 Karrer P, Hofmann A. Polysaccharide XXXIX. Über den enzymatischen Abbau von Chitin und Chitosan I.  Helv Chim Acta. 1929;  12 616-37
• 2 Stoll A, Suter E, Kreis W, Bussemaker B B, Hofmann A. Die herzaktiven Substanzen der Meerzwiebel. Scillaren A. (1. Mitteilung über Herzglucoside).  Helv Chim Acta. 1933;  16 703-33
• 3 Stoll A, Hofmann A, Kreis W. Über Scillarenase. (3. Mitteilung über Herzglucoside).  Hoppe-Seylers Zeitschr Physiol Chemie. 1935;  235 249-64
• 4 Stoll A, Hofmann A, Helfenstein A. Die Identität der α-Scillansäure mit Allocholsäure. 11. Mitteilung über Herzglucoside.  Helv Chim Acta. 1935;  18 644-659
• 5 Stoll A, Hofmann A. Partialsynthese des Ergobasins, eines natürlichen Mutterkornalkaloids sowie seines optischen Antipoden. (3. Mitteilung über Mutterkornalkaloide).  Hoppe-Seylers Zeitschr Physiol Chemie. 1938;  251 155-63
• 6 Stoll A, Hofmann A. Partialsynthese von Alkaloiden vom Typus des Ergobasins. (6. Mitteilung über Mutterkornalkaloide).  Helv Chim Acta. 1943;  26 944-65
• 7 Hofmann A. LSD – mein Sorgenkind. Stuttgart; Klett-Cotta 1979 (English translation: LSD – My Problem Child. New York: McGraw-Hill; 1980)
• 8 Stoll A, Hofmann A. Die Alkaloide der Ergotoxingruppe: Ergocristin, Ergokryptin und Ergocornin. (7. Mitteilung über Mutterkornalkaloide).  Helv Chim Acta. 1943;  26 1570-1603
• 9 Stoll A, Hofmann A. Die Dihydroderivate der natürlichen linksdrehenden Mutterkornalkaloide. (9. Mitteilung über Mutterkornalkaloide).  Helv Chim Acta. 1943;  26 2070-81
• 10 Stoll A, Hofmann A, Troxler F. Über die Isomerie von Lysergsäure und Isolysergsäure. 14. Mitteilung über Mutterkornalkaloide.  Helv Chim Acta. 1949;  32 506-521
• 11 Stoll A, Petrzilka T, Rutschmann J, Hofmann A, Günthard H H. Über die Stereochemie der Lsysergsäuren und der Dihydro-lysergsäuren. 37. Mitteilung über Mutterkornalkaloide.  Helv Chim Acta. 1954;  37 2039-57
• 12 Stoll A, Hofmann A, Petrzilka T. Die Konstitution der Mutterkornalkaloide. Struktur des Peptidteils. III. 24. Mitteilung über Mutterkornalkaloide.  Helv Chim Acta. 1951;  34 1544-76
• 13 Hofmann A, Ott H, Frey A J. Die Totalsynthese des Ergotamins.  Experientia. 1961;  17 206-7
• 14 Hofmann A, Ott H, Griot R, Stadler P A, Frey A J. Die Synthese und Stereochemie des Ergotamins. (58. Mitteilung über Mutterkornalkaloide).  Helv Chim Acta. 1963;  46 2306-28
• 15 Troxler F, Hofmann A. Substitutionen am Ringsystem der Lysergsäure. III. Halogenierung. 45. Mitteilung über Mutterkornalkaloide.  Helv Chim Acta. 1957;  40 2160-70
• 16 Stoll A, Brack A, Kobel H, Hofmann A, Brunner R. Die Alkaloide eines Mutterkornpilzes von Pennisetum typhoideum Rich. Und deren Bildung in saprophytischer Kultur. 36. Mitteilung über Mutterkornalkaloide.  Helv Chim Acta. 1954;  37 1815-25
• 17 Hofmann A, Brunner R, Kobel H, Brack A. Neue Alkaloide aus der saprophytischen Kultur des Mutterkornpilzes von Pennisetum typhoideum Rich. 42. Mitteilung über Mutterkornalkaloide.  Helv Chim Acta. 1957;  40 1358-73
• 18 Stoll A, Hofmann A. Sarpagin, ein neues Alkaloid aus Rauwolfia serpentina Benth. Helv.  Chim Acta. 1953;  36 1143-7
• 19 Hofmann A, Heim R. Brack A, Kobel. Psilocybin, ein psychotroper Wirkstoff aus dem mexikanischen Rauschpilz Psilocybe mexicana Heim.  Experientia. 1958;  14 107-9
• 20 Hofmann A, Heim R. Brack A, Kobel H, Frey A, Ott H et al. Psilocybin und Psilocin, zwei psychotrope Wirkstoffe aus mexikanischen Rauschpilzen.  Helv Chim Acta. 1959;  42 1557-72
• 21 Hofmann A, Tscherter H. Isolierung von Lysergsäure-Alkaloiden aus der mexikanischen Zauberdroge Ololiuqui (Rivea corymbosa (L.) Hall F.  Experientia. 1960;  16 414
• 22 Hofmann A. Ein neuer Süssstoff aus der Indolreihe.  Helv Chim Acta. 1972;  55 2934-40
• 23 Hofmann A. Die Mutterkornalkaloide. Stuttgart; Ferdinand Enke Verlag 1964
• 24 Hofmann A. Einsichten – Ausblicke. Solothurn; Nachtschatten Verlag 2003 (Original edition: Basel: Sphinx; 1986). (English translation: Insight – Outlook. Atlanta: Humanics; 1989)
• 25 Hofmann A. Lob des Schauens. Solothurn; Nachtschatten Verlag 2003
• 26 Engel G, Herrling P. (eds.) .Grenzgänge – Albert Hofmann zum 100. Geburtstag. Exploring the Frontiers – in Celebration of Albert Hofmann’s 100^th Birthday. Basel; Schwabe Verlag 2006